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No 8736Saturday 2 February 1991

ORIGINALARTICLES

Children born to women with HIV-1 infection:natural history and risk of transmission

EUROPEAN COLLABORATIVE STUDY*

*Prepared by Dr A. E.Ades, PhD, Dr M L. Newell, MB, Prof C. S.Peckham, MD (coordinating centre), Department of Paediatric

Epidemiology, Institute of Child Health, 30 Guilford Street,London WC1 N 1 EH, U K.

Collaborators Dr C. Giaquinto, Prof F. Zacchello, Dr A. De Rossi, ProfL. Chieco-Bianchi (Universita degli Studi di Padova, Italy); Dr I.Grosch-Wrner, Dr S. Koch (Freie Universitat, UniversittsklinikumRudolf Virchow, West Berlin), Dr J Y Q. Mok, Dr R Hague (CityHospital, Edinburgh, UK), Dr F. Omeaca Teres, Dr M. C. Garcia

Rodriguez, Dr R Martinez-Zapico, Dr M. I. de Jose, Dr G. Fontan

Casariego (Hospital Infantil La Paz, Madrid, Spain), Dr C.ACanosa, DrM. C Otero, Dr D. Perez Tamarit, Dr D Granda, Dr M Gobernado, Dr A.

Gonzalez Molina (Departamentode Pediatria "La Fe", Valencia, Spain);Dr H. J Scherpbier, (Academisch Medisch Centrum,Amsterdam, theNetherlands), DrA B. Bohlin, Dr M. Forsgren (Department ofPaediatrics, Huddinge Hospital and Central Microbiological Laboratory,Stockholm, Sweden), Dr A Ferrazin, Dr A De Maria, Dr C Gotta, Prof A

Terragna (I Clinica Mallattie Infettive Universit, Istituto G. Gaslini,Genova, Italy), Dr J. Levy (Hospital St Pierre, Brussels, Belgium); ProfJ. Llorens-Terol, Dr A. Mur, Dr H Yazbeck, Dr F. Prats (Hospital del Mar,Barcelona, Spain).

Correspondence to Prof C. S. Peckham.

600 children born to HIV-infected mothers by June15, 1990, in ten European centres were followed to

study the natural history of HIV infection and thevertical transmission rate. They were seen at birth,

every3months up

to18 months

ofage,

andevery

6

months thereafter.At last follow-up, 64 childrenwere judged to be HIV infected and 343 had lost

antibody and were presumed uninfected. The initialclinical feature in infected children was usually acombination of persistent lymphadenopathy,splenomegaly, and hepatomegaly, though 30% ofchildren presented with AIDS, or with oralcandidosis followed rapidly byAIDS.An estimated83% of infected children show laboratory or clinicalfeatures of HIV infection by 6 months of age. By 12months, 26% haveAlDS and 17% die of H IV-related

disease. Subsequently, the disease progresses moreslowly and most children remain stable or even

improve during the second year. The verticaltransmission rate, based on results in 372 children

born at least 18 months before the analysis, was129% (95% Cl 95-163%). Virus has been

repeatedly isolated in an additional small proportionof children (25%, 95% Cl 07-63%) who lost

maternal antibody and have remained clinically and

immunologically normal. Without a definitive

virological diagnosis, the monitoring of immuno-

globulins, CD4/CD8 ratio, and clinical signs could

identify HIV infection in 48% of infected childrenby 6 months, with a specificity of more than 99%.

Introduction

Knowledge of the natural history of vertically acquiredhuman immunodeficiency virus-1(HIV-1) is based mainlyon studies of children presenting with symptoms to

specialist centres.l-6 Prospective studies ofverticallyinfectedchildren should provide a more accurate understanding/-9though increasing use of treatment could bias results.Information about earlier or less severe features of the

disease and its progressionis needed for the designofclinical

trails, and to assist in management and early diagnosis ofinfected children. The European Collaborative Study(ECS) is a prospective study of children born to HIV-infected mothers .10-12 We here report results relating to the

natural history of HIV infection and the vertical

transmission rate.

Children and methods

By June 15, 1990, 600 children bom to HIV-1 seropositivemothers had been recruited and followed from birth in ten

European centres (Padua, Berlin, Edinburgh, Madrid, Valencia,Amsterdam, Stockholm, Genoa, Brussels, Barcelona). Children

were included only iftheir mothers were known to be infected at orbefore delivery; all such children were included.1O-12

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recognise 48% of infected infants by 6 months. None of the325 children who lost antibody and who were followed forover 12 months met this criterion in the first 12 months. The

specificity is therefore estimated to be 100% and with this

sample size is unlikely to be less than 99-1% (lower 90%

confidence limit).

Vertical transmission rate

Of 419 children born 18 months or more before June 15,1990, 372 were of known infection status and of these 48were infected (table ]). This represents a transmission rate of

12-9% (95% CI 9-5-16-3%), which agrees closely with theestimate of the surviving fraction of 13-4% in fig 2. Therewere no statistically significant differences in transmissionrates between centres, nor were there changes over time. Ofthe 353 children who lost antibody, virus isolation had been

attempted in 163; in 10 (6-1%), positive results were

obtained at least once. With the exception of 1 child in whoma static encephalopathy uncharacteristic ofHIV developedfollowing a Reye-like syndrome/2,15 these 10 children didnot seem to differ clinically or immunologically from theother 343 children who lost antibody. 1 child had hyper-IgG, another a low T4/T8 ratio, and a thirdlymphadenopathy and hepatomegaly. However, these signsall resolved within a few months, and taken together theyrepresent an incidence of the same order as would be

expected in children who lost antibody. In 4 children theinitial positive culture was confirmed on subsequentsamples by repeat virus culture and/or polymerase chain

reaction (PCR). But in the remaining 6, a total of eighteenattempted cultures were negative, and laboratory error orcontamination cannot be completely ruled out. The data do

not, therefore, support an estimate greater than 4/163(2-5%,95% CI 0-7-6-3%).

Discussion

As a description of the natural historyofHIV-1 infection

up to diagnosisofAIDS in the first 3 years of life, we believethat the ECS is substantially unbiased by treatment. While

confirming the wide spectrum of disease found by other

investigators,-, 9,16-23 the ECS provides additional

information on the timing of initial symptoms, and thefrequencies of clinical and immunological features.

Birthweight, gestation, head circumference at birth, or

birthweight adjusted for gestation did not discriminatebetween infected and uninfected children; this alsoconfirms earlier results.7,1l The lower birthweight ofchildren born to women withAIDS or with symptomlessHIV infection than of those born to seronegative women

reported in twoAfrican-based studies2224 is more likely to bedue to differences in the mothers socioeconomic or health

circumstances than to interuterine infection, since these

findings have not been seen in New York 25 or Scotland.26

Our findings show that without a definitive diagnosis,immunological and clinical signs can be regarded as

predictors of HIV infection in children under 18 monthsold.Although several signs and symptoms are associatedwith HIV infection, the ECS shows that many are not

specific enough to be useful markers either of infection or ofthe development ofAIDS. Otitis media, rhinitis, non-

cryptosporidium diarrhoea and unexplained fever were all

poor indicators of infection compared with hyper-IgG,A,M, which identified 77% of infected children at 6months with 97% specificity. Inapopulation ofwhom 15%

are infected, this implies a positive predictive value of only80%, and may not therefore be an indication for therapieswith side-effects.Acombination of any two of hyper-IgG,A,M, low T4/T8 ratio, or HIV-ISS was highly specificand could be used as a criterion for treatment or inclusion in

a

therapeutictrial.

However,these

findingsshould not be

applied to children whose mothers are not known to be

positive, because immunological signs could have very low

predictive value in the general population. Moreover, our

findings would not be applicable in countries where

hyper-IgG, lymphadenopathy, and hepatosplenomegaly,due to chronic infections are common. 27 The relative

frequency ofAIDS indicator diseases in the ECS is similarto earlier reports.7.2028 The possible association betweenfailure-to-thrive and encephalopathy would point to acentral nervous system mechanism for failure-to-thrive that

is different from the opportunistic diarrhoeal infections that

probably underlie failure-to-thrive inAfrican studies.

Our findings have implications for clinical managementand for the design of clinical trials. Firstly, treatment willhave to be started very early-within the first 2 or 3months-to prevent the early onset ofAIDS in about 30%of infected children.7 Except in laboratories with highexpertise, such an early diagnosiswould be hard to achieve at

present.Also, during the second and third years of life, the

progression of HIV disease seems to be slow, with morechildren improving than deteriorating. Long-termtreatment of symptom-free children or those with mild

symptoms may be necessary to show any benefit; this not

only creates difficulties in the design of trials for treatments

with side-effects, but also raises doubts about earlier, opentherapeutic studies that attributed to treatment

improvements that might have occurred spontaneously.z9.3oOur 13% estimated transmission rate is lower than rates

published in all but one study,31 which was a subset of theECS. It is possible that a higher frequency of risk factorssuch as breastfeeding or mothers clinical condition couldaccount for these differences. However, estimates in manyearlier studies may have been biased upwards. For example,in one study, virus cultured from cord blood was taken as

proof of infection.22 In a study citing 39% transmission,47% of the cohort had been lost to follow-up;24 and those

remaining may have been more likely to have been ill.A29% rate was cited in a New York Study.32 However, that

analysis included antibody-negative children only if theyhad been followed for 15 months, whereas infected childrenwere included with shorter follow-up. In studies in whichsome children are recruited retrospectively, the requirementthat the mother shouldbe seropositive may be insufficient to

prevent a bias towards selective recruitment ofsick children.

Afurther requirement is that collaborating centres report allchildren born to seropositive mothers. This type ofbias mayhave occurred in the Italian Multicentre Study" (33%transmission), which is register based; in the French Study,/which has 51

collaboratingcentres

(27% transmission);and

also in earlier reports from the ECS.lO,l1 The requirementfor inclusion in the transmission rate that children should

have an antibody test after 18 months"rather than have abirth date 18 months earlier also biases estimates upwardsbecause parents ofchildren who lose antibody earlier are less

likely to bring the children back for continuing follow-up.Even if all the children who were lost to follow-up were

infected, the transmission rate would still only be 23%.

Deaths in children of indeterminate infection status, of

which there were 7 in the ECS, also make the calculations of